Naturally occurring antibodies (Igs) can be considered as nature's optimized targeting molecule with elegant structural features and remarkable specificity. Ig-target interactions also provide insights into the biochemical and structural properties of a successful molecular probe and offer a guideline towards innovative design of novel molecules for therapy and imaging. Nucleic acid aptamers (nucleic acid based antibody analogues) are being investigated to develop therapeutic molecules for cancer. In order to develop aptamers as successful therapeutic molecules, it is necessary to generate aptamers for known specific targets. Currently, target specific aptamers are selected using over-expressed protein either on a cell or as a purified protein, which may not recognize the targeting epitope when the protein is expressed at its native levels, in its native environment. Recently introduced cell-SELEX method allows the selection of aptamers towards membrane targets at their native state. We will introduce an innovative and novel technology based on cell-SELEX method, for the first time, in this proposal, which will allow selection of aptamers specific for pe-determined epitopes of a receptor molecule in their native state, guided by antibody-antigen interactions. Introduction of this new technology will be of significant, because this method will improve the existing methodology of selecting aptamers towards a broader range of cell receptor molecules that have an antibody or a ligand. We will test this technology by conducting two different aptamer selections. These two targets are: (1) A pre-determined epitope of T-cell receptor complex (TCR), (2) A pre-determined epitope of B-cell receptor complex (BCR). Selected anti-TCR and anti-BCR aptamers will be engineered into DNA based synthetic antibodies that mimic bi- and mono-specific native antibodies. Upon completion of this project we will have (1) A new SELEX technology to select aptamers that can be customized towards a known epitope, (2) A new class of synthetic antibody mimics based on DNA aptamers that will have therapeutic applications in disease areas such as cancer and autoimmune diseases.